Endothelial cells play an important role in determining the risk for atherosclerosis and coronary artery disease[unreadable] (CAD). Exercise may restore/preserve a healthy endothelium and limit atherosclerosis. An important part of[unreadable] this project will be to determine in a well-controlled porcine model, the effects of exercise on the expression[unreadable] of a group of proteins known to have a central role in determining the risk of vascular disease. The[unreadable] experiments are focused on a set of putative PPAR-responsive mRNAs/proteins and lipoprotein lipase (LPL).[unreadable] LPL is a rate-limiting enzyme for the metabolism of triglyceride-rich lipoproteins, and as such, high levels of[unreadable] LPL activity have been associated with the metabolic demands of exercise. The effect of LPL-dependent[unreadable] lipolysis on the phenotype of endothelial cells is still largely unclear and needs to be elucidated. A strength[unreadable] of these experiments is that they employ a multifaceted and collaborative approach to accomplish a definitive[unreadable] set of hypothesis-driven studies. Molecular studies will determine the mRNA and protein targets regulated[unreadable] directly by LPL-dependent signaling in endothelial cells (Aim 1). This aim will use a wide-range of[unreadable] experimental culture conditions involving different amounts of LPL activity, purified lipoprotein substrates, RNA[unreadable] interference for signaling studies, and pharmacological ligands to compare with lipoprotein derived ligands.[unreadable] Aim 1 will also test for interactions during exposure to TNFa as a pro-inflammatory cytokine. More[unreadable] physiological studies will be performed in isolated conduit arteries while determining the interactions between[unreadable] chemical signals caused by experimentally reducing and increasing LPL activity, and the hemodynamic[unreadable] signaling caused by altering flow rate over a wide range (Aim 2). Exercise training studies will determine how[unreadable] LPL and a group of related proteins are regulated in different vascular sites (Aim 3). Aim 3 will be a very[unreadable] complete examination of exercise responses because it will determine the effects of training in pigs fed a[unreadable] normal fat diet before there is a risk of CAD, in a model of risk for early CAD, and in more advanced CAD.[unreadable] These studies will provide important novel insights about regulation of LPL activity, and the mechanisms[unreadable] involved in determining a healthy endothelial cell phenotype.